Project 6 Project 6 proposes novel clinical trials to reduce non-leukemic mortality associated with allogenic HSCT for treatment of leukemias and myelodysplasia (MDS), particularly in older patients and in patients lacking an HLA-matched sibling donor and to treat post transplantation viral disease and leukemic relapse. There are 6 clinical trials under 2 specific aims. Aim1 includes 3 phase II clinical trials of TCD grafts to speed marrow and immune reconstitution. Aim 1A will evaluate the ability of TCD-PBSC (CliniMACS) given after one of 2 reduced intensity regimens using only chemotherapy, as compared to our standard high intensity, TBI containing regimen to secure consistent engraftment, low rates of GVHD, TRM and relapse and high DFS. Aim 18 clinically translates Dr. van den Brink's studies done during this grant period to use palifermin and leuprolide to protect the thymic stroma and promote early, robust recovery of T cell immunity, thereby reducing TRM due to infection in older patients (median age >50). Aim IC, also derived from trials conducted in the current grant, will evaluate whether addition of haplotype disparate TCD-PBSC to a double cord blood (CB) graft provides earlier hematopoietic reconstitution, thereby reducing early TRM while maintaining the low incidence of relapse observed following double CB grafts. Aim 2 includes 3 trials of adoptive cellular therapy. Effective prevention of GVHD, as developed at our center, allows for adoptive cell therapies in the absence of post-transplant immuno-suppressive drugs to prevent GVHD. Aim 2A is a 2- armed Phase II extension ofthe Phase I trial conducted in the current grant period to evaluate treatment of CMV infections with a) CMVpp65-specific T-cells derived from seropositive HSCT donors of b) partially HLA matched 3rd party CMV-CTL for patients receiving CBs or transplants from CMV seronegative donors. Aim 2B derives from studies conducted in the current grant and extends our Phase I trial of single dose WT1 -CTL to multiple dosing for treatment of patients with recurrence of WT-1 + leukemias. Aim IC is a phase I trial of donor-derived EBV-CTL transduced to express a CD19-specific chimeric antigen receptor for the treatment of GDI 9+ leukemias.